Taglin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TAGLIN (TAGLIN)

Composition:

Active substance: vildagliptin;

1 tablet contains 50 mg of vildagliptin;

Excipients: microcrystalline cellulose, anhydrous lactose, sodium starch glycolate (type A), magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round, flat tablets.

Pharmacotherapeutic group. Antihyperglycemic agents, excluding insulin. Dipeptidyl peptidase-4 inhibitors. ATC A10B H02.

Pharmacological properties.

Pharmacodynamics.

Vildagliptin belongs to the class of substances that enhance the function of pancreatic islet beta cells and is a potent and selective inhibitor of dipeptidyl peptidase-4 (DPP-4).

Administration of vildagliptin results in rapid and complete inhibition of DPP-4 activity. Inhibition of DPP-4 by vildagliptin increases endogenous levels of incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) during fasting and after food intake.

As a result of increased endogenous levels of these incretin hormones, vildagliptin improves beta-cell sensitivity to glucose, leading to enhanced glucose-dependent insulin secretion. Treatment of patients with type II diabetes with vildagliptin at doses of 50 to 100 mg daily significantly improved markers of beta-cell function, including HOMA-β (homeostatic model assessment of beta-cell function), proinsulin-to-insulin ratio, and beta-cell sensitivity indices during repeated meal tolerance tests. In non-diabetic individuals (with normal blood glucose levels), vildagliptin does not stimulate insulin secretion or reduce glucose levels.

Due to increased endogenous GLP-1 levels, vildagliptin also enhances alpha-cell sensitivity to glucose, resulting in increased glucose-dependent glucagon secretion. The significant increase in the insulin-to-glucagon ratio during hyperglycemia, driven by elevated incretin hormone levels, leads to reduced glucose production during fasting and after meals, thereby lowering glycemia.

The known effect of elevated GLP-1 levels to delay gastric emptying is not observed during treatment with vildagliptin.

Pharmacokinetics.

Absorption

After oral administration in the fasting state, vildagliptin is rapidly absorbed, with C_max reached at 1.7 hours. Co-administration with food slightly delays the time to reach C_max in plasma to 2.5 hours but does not affect total exposure (AUC). Administration of vildagliptin with food results in a 19% reduction in maximum concentration (C_max). Despite this, the magnitude of changes is not considered clinically significant; therefore, vildagliptin can be administered independently of food intake. Absolute bioavailability is 85%.

Distribution

The plasma protein binding of vildagliptin is low (9.3%); vildagliptin is evenly distributed between plasma and erythrocytes. The mean steady-state volume of distribution after intravenous administration (V_ss) is 71 L, indicating extensive extravascular distribution.

Metabolism

Metabolism is the main route of elimination of vildagliptin in humans, accounting for 69% of the administered dose. The primary metabolite, LAY151, is pharmacologically inactive and results from hydrolysis of the cyanopyrrolidine moiety, representing 57% of the dose, along with glucuronide (BQS867) and amide hydrolysis (4% of dose). Data from in vitro studies using human kidney microsomes indicate that the kidneys may be one of the main organs contributing to the hydrolysis of vildagliptin to its primary inactive metabolite, LAY151. DPP-4 partially participates in the hydrolysis of vildagliptin, as confirmed by in vivo studies in DPP-4-deficient rats.

Vildagliptin is not metabolized to any significant extent by cytochrome P450 enzymes. Therefore, concomitant administration of medicinal products such as inhibitors and/or inducers of CYP450 is not expected to affect the metabolic clearance of vildagliptin. In vitro studies have shown that vildagliptin neither inhibits nor induces cytochrome P450 enzymes. Thus, vildagliptin is unlikely to affect the metabolic clearance of concomitantly administered medicinal products metabolized by CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5.

Excretion

After oral administration of [14C]-vildagliptin, approximately 85% of the dose is excreted in urine and 15% in feces. Renal excretion of unchanged vildagliptin accounts for 23% of the orally administered dose. After intravenous administration to healthy volunteers, total plasma and renal clearance of vildagliptin are 41 L/h and 13 L/h, respectively. The mean elimination half-life after intravenous administration is approximately 2 hours. The elimination half-life after oral administration is approximately 3 hours.

Linearity/Non-linearity

The maximum plasma concentration (C_max) and the area under the plasma concentration-time curve (AUC) of vildagliptin increase almost proportionally with dose across the entire therapeutic dose range.

Special patient populations

Gender

No differences in the pharmacokinetics of the drug were observed between healthy male and female volunteers of various ages and body mass index (BMI). Inhibition of DPP-4 by vildagliptin is independent of patient gender.

Hepatic impairment

The effect of impaired liver function on the pharmacokinetics of vildagliptin was studied in patients with mild, moderate, and severe hepatic impairment based on Child-Pugh classification (scores ranging from 6 for mild to 12 for severe impairment), compared to patients with normal liver function. Exposure to vildagliptin after a single dose was reduced in patients with mild and moderate hepatic impairment (by 20% and 8%, respectively), whereas exposure increased by 22% in patients with severe hepatic impairment. The maximum change (increase or decrease) in vildagliptin exposure was approximately 30%, which is not considered clinically significant. No correlation was observed between the severity of hepatic impairment and changes in vildagliptin exposure.

Renal impairment

An open-label, multiple-dose study was conducted to evaluate the pharmacokinetics of the lowest therapeutic dose of vildagliptin (50 mg once daily) in patients with varying degrees of chronic renal impairment, as determined by creatinine clearance (mild renal impairment: 50 to < 80 mL/min; moderate renal impairment: 30 to < 50 mL/min; severe renal impairment: < 30 mL/min), compared to a control group of study participants with normal renal function.

In patients with mild, moderate, and severe renal impairment, AUC of vildagliptin was increased compared to patients with normal renal function. AUC values for metabolites LAY151 and BQS867 increased on average by approximately 1.5-, 3-, and 7-fold in patients with mild, moderate, and severe renal impairment, respectively. Limited data in patients with end-stage renal disease (ESRD) show that vildagliptin exposure is similar to that in patients with severe renal impairment. Concentrations of LAY151 were approximately 2–3 times higher than in patients with severe renal impairment.

Vildagliptin was eliminated to a limited extent by hemodialysis (3% over a 3–4 hour hemodialysis session initiated 4 hours after drug administration).

Elderly patients

In otherwise healthy patients aged 70 years and older, total exposure to vildagliptin (100 mg once daily) increased by 32%, and maximum plasma concentration increased by 18%, compared to younger healthy volunteers (aged 18 to 40 years).

However, these changes are not considered clinically significant. Inhibition of DPP-4 by vildagliptin is independent of patient age within the studied age groups.

Race

Limited data indicate that race does not have a significant impact on the pharmacokinetics of vildagliptin.

Clinical characteristics.

Indications.

Vildagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus:

– as monotherapy in patients in whom the use of metformin is considered unacceptable due to contraindications or intolerance;

– in combination with other antidiabetic medicinal products, including insulin, when they do not provide adequate glycemic control (for available data on various combinations, see sections "Pharmacological properties", "Interaction with other medicinal products and other forms of interaction", and "Special precautions for use").

Contraindications.

Known hypersensitivity to vildagliptin or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

Vildagliptin has a low potential for interaction with other drugs. Since vildagliptin is not a substrate of cytochrome P450 (CYP) enzymes and is neither an inhibitor nor an inducer of CYP450 enzymes, clinically relevant interactions with other drugs that are substrates, inhibitors, or inducers of these enzymes are unlikely.

Combination with pioglitazone, metformin, and glyburide

Clinical studies conducted with these oral antidiabetic agents did not reveal clinically significant pharmacokinetic interactions.

Digoxin (Pgp substrate), warfarin (CYP2C9 substrate)

Clinical studies conducted in healthy volunteers did not show clinically significant pharmacokinetic interactions. However, this has not been established in the target population.

Combination with amlodipine, ramipril, valsartan, or simvastatin

Drug interaction studies in healthy volunteers have been conducted with amlodipine, ramipril, valsartan, and simvastatin. In these studies, no clinically significant pharmacokinetic interactions were observed after concomitant administration of these agents with vildagliptin.

Combination with ACE inhibitors

An increased risk of angioedema may occur in patients taking ACE inhibitors concomitantly (see section "Adverse reactions").

As with other oral antidiabetic agents, certain active substances, including thiazides, corticosteroids, thyroid hormones, and sympathomimetics, may reduce the hypoglycemic effect of vildagliptin.

Special precautions.

General

Vildagliptin is not a substitute for insulin in insulin-dependent patients. The drug should not be used for the treatment of patients with type 1 diabetes or diabetic ketoacidosis.

Renal impairment

Experience with vildagliptin in patients with moderate or severe renal impairment, as well as in patients with end-stage renal disease (ESRD) on hemodialysis, is limited. Therefore, the use of the drug is not recommended in these patient groups (see sections "Pharmacological properties" and "Dosage and administration").

Hepatic impairment

Vildagliptin is not recommended for use in patients with hepatic impairment, including patients whose baseline levels of ALT or AST are more than 3 times the upper limit of normal (see sections "Pharmacological properties" and "Dosage and administration").

Monitoring of liver enzymes

Rare cases of liver function abnormalities (including hepatitis) have been reported. In such cases, the course was mostly asymptomatic, without clinical consequences, and liver function test (LFT) results returned to normal after discontinuation of treatment. Before initiating treatment with the drug, LFTs should be performed to establish baseline values in the patient. Monitoring of LFT results should be performed during treatment with the drug for the first year of treatment at intervals of every 3–4 months, and periodically thereafter.

For patients in whom elevated transaminase levels have been observed, repeat monitoring of liver function should be performed to confirm results, as well as continued monitoring with more frequent liver function testing until abnormal levels return to normal. If ALT or AST levels increase to 3 times or more above the upper limit of normal, discontinuation of the drug is recommended. Patients who develop jaundice or other signs of hepatic dysfunction should discontinue use of the drug. After discontinuation of treatment with the drug and normalization of LFT results, treatment with vildagliptin should not be restarted.

Heart failure

A clinical study of vildagliptin use in patients with NYHA functional class I–III heart failure showed that treatment with vildagliptin was not associated with changes in left ventricular function or worsening of existing congestive heart failure. Clinical experience with use in patients with NYHA functional class III heart failure remains limited and results are inconclusive.

There is no clinical experience with the use of vildagliptin in patients with NYHA functional class IV heart failure; therefore, the drug is not recommended for use in these patients.

Skin disorders

In preclinical toxicological studies, skin lesions including blistering and ulceration on extremities were reported in monkeys. Although no increased incidence of skin lesions was observed during clinical trials, experience regarding skin complications in patients with diabetes mellitus is limited.

Additionally, during the post-marketing period, cases of bullous and exfoliative skin lesions have been reported.

Therefore, in accordance with standard care for patients with diabetes mellitus, monitoring for skin disorders such as blistering or ulceration is recommended.

Pancreatitis

The use of vildagliptin is associated with a risk of developing acute pancreatitis. Patients should be informed about the typical symptoms of acute pancreatitis.

If pancreatitis is suspected, vildagliptin should not be continued. If acute pancreatitis is confirmed, vildagliptin should not be restarted. Caution should be exercised in patients with a history of acute pancreatitis.

Hypoglycemia

Sulfonylureas are known to cause hypoglycemia. Patients receiving vildagliptin in combination with a sulfonylurea may be at increased risk of hypoglycemia. Therefore, lower doses of sulfonylurea may be considered to reduce the risk of hypoglycemia.

Other

The drug contains lactose. If a patient has known intolerance to certain sugars, consultation with a physician is necessary before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

There are no adequate studies on the use of vildagliptin in pregnant women.

Animal studies have shown reproductive toxicity when high doses of the drug were administered. The potential risk to humans is unknown. Due to the lack of data, the drug should not be used during pregnancy.

Breastfeeding

It is unknown whether vildagliptin passes into human breast milk. Animal studies have shown excretion of vildagliptin into animal milk. The drug should not be administered to women who are breastfeeding.

Fertility

Studies on the effect of vildagliptin on human fertility have not been conducted.

Effect on ability to drive and use machines.

Studies on the effect of the drug on the ability to drive or operate machinery have not been conducted. Patients who experience dizziness should not drive or operate machinery.

Method of Administration and Dosage

When used as monotherapy, in combination with metformin, in combination with a thiazolidinedione, in combination with metformin and a sulfonylurea, or in combination with insulin (with or without metformin), the recommended daily dose of vildagliptin is 100 mg, divided into two doses: 50 mg in the morning and 50 mg in the evening.

When used in combination with a sulfonylurea, the recommended dose of vildagliptin is 50 mg once daily in the morning. In this patient population, vildagliptin at a dose of 100 mg daily was not more effective than vildagliptin at a dose of 50 mg once daily.

When used in combination with a sulfonylurea, to reduce the risk of hypoglycemia, it may be possible to use lower doses of the sulfonylurea.

Doses exceeding 100 mg of the drug are not recommended.

If a dose is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.

The safety and efficacy of vildagliptin in triple oral therapy in combination with metformin and a thiazolidinedione have not been established.

Dosing in Patients with Hepatic or Renal Impairment

The drug is not recommended for use in patients with hepatic impairment, including patients whose baseline ALT or AST levels are more than three times the upper limit of normal.

For patients with mild renal impairment (creatinine clearance ≥ 50 mL/min), no dose adjustment is required. For patients with moderate or severe renal impairment or with end-stage renal disease (ESRD), the recommended dose is 50 mg once daily.

Dosing in Elderly Patients

No dose adjustment is required for patients aged 65 years and older.

Dosing in Children

The use of the drug is not recommended in children and adolescents under 18 years of age due to lack of data on safety and efficacy.

Method of Administration

For oral administration.

The drug can be administered independently of food intake.

Children

The use of the drug is not recommended in children and adolescents under 18 years of age due to lack of data on safety and efficacy.

Overdose

Information regarding vildagliptin overdose is limited.

Symptoms

Information on possible overdose symptoms was obtained from a dose-tolerance study in healthy volunteers who received vildagliptin for 10 days. At a dose of 400 mg, three cases of muscle pain were observed, along with several cases of mild and transient paresthesia, fever, development of edema, and temporary elevation of lipase levels. At a dose of 600 mg, one volunteer developed swelling of the legs and arms, marked elevation of creatine phosphokinase (CPK) levels, accompanied by increased AST, C-reactive protein, and myoglobin levels. Three volunteers in this group developed bilateral leg edema, which was accompanied by paresthesia in two cases. All symptoms and laboratory abnormalities resolved after discontinuation of the investigational drug.

Treatment

In case of overdose, supportive therapy is recommended. Vildagliptin is not eliminated by hemodialysis; however, most hydrolysis metabolites (LAY 151) can be removed by hemodialysis.

Adverse reactions.

Data on the safety of the drug were obtained from double-blind, placebo-controlled studies of at least 12 weeks’ duration involving a total of 5451 patients receiving vildagliptin at a daily dose of 100 mg (50 mg twice daily). Of these patients, 4662 received vildagliptin as monotherapy and 829 received placebo.

The majority of adverse reactions occurring during clinical studies were mild in nature, transient, and did not require discontinuation of treatment. There was no observed association between the development of adverse reactions and patient age or race, duration of drug intake, or daily dose.

Hypoglycemia was reported in patients receiving vildagliptin concomitantly with sulfonylurea derivatives and insulin. There have been reports of risk of acute pancreatitis with the use of vildagliptin (see section "Special precautions").

Adverse reactions observed during double-blind studies in patients receiving vildagliptin as monotherapy and in combination therapy are listed below for each system organ class and absolute frequency. Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (> 1/10000, ≤ 1/1000), very rare (≤ 1/10000), frequency not known (cannot be estimated based on available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Adverse reactions recorded in patients receiving vildagliptin at a dose of 100 mg per day as monotherapy during double-blind studies

Table 1

System organ	Adverse reactions and frequency
Infections and infestations
Nasopharyngitis	Very common
Upper respiratory tract infections	Common
Metabolism and nutrition disorders
Hypoglycemia	Uncommon
Nervous system disorders
Dizziness	Common
Headache	Common
Tremor	Common
Eye disorders
Blurred vision	Common
Gastrointestinal disorders
Constipation	Common
Nausea	Common
Gastroesophageal reflux disease	Common
Diarrhea	Common
Abdominal pain, including upper abdominal pain	Common
Vomiting	Common
Flatulence	Uncommon
Pancreatitis	Rare
Hepatobiliary disorders
Hepatitis	Frequency unknown*
Skin and subcutaneous tissue disorders
Hyperhidrosis	Common
Rash	Common
Pruritus	Common
Dermatitis	Common
Urticaria	Uncommon*
Exfoliative and bullous skin reactions, including bullous pemphigoid	Frequency unknown*
Skin vasculitis	Frequency unknown
Musculoskeletal and connective tissue disorders
Arthralgia	Common
Myalgia	Common
Reproductive system disorders
Impotence	Uncommon
General disorders
Asthenia	Common
Peripheral edema	Common
Fatigue	Uncommon
Chills	Uncommon
Investigations
Abnormal liver function tests	Uncommon
Weight increased	Uncommon
*based on post-marketing experience

Description of individual adverse reactions

Hepatic function disorders

Rare cases of hepatic function disorders (including hepatitis) have been reported. These disorders were observed to be asymptomatic without clinical consequences, and liver function returned to normal after discontinuation of treatment. According to data from controlled monotherapy and combination therapy studies up to 24 weeks, the incidence of ALT or AST levels elevation ≥ 3 × ULN (classified as present in at least two consecutive measurements or at the last treatment visit) was 0.2% for vildagliptin 50 mg once daily, 0.3% for vildagliptin 50 mg twice daily, and 0.2% for all comparator agents. Such transaminase elevations were asymptomatic, non-progressive in nature, and not associated with cholestasis or jaundice.

Angioedema

Rare cases of angioedema have been reported with vildagliptin use, occurring at the same frequency as in the control group. A higher number of cases was reported when vildagliptin was administered in combination with an angiotensin-converting enzyme (ACE) inhibitor. Most cases were mild and resolved with continued vildagliptin administration.

Hypoglycemia

In comparative controlled monotherapy studies, hypoglycemia was infrequent and occurred in 0.4% of patients receiving vildagliptin as monotherapy, compared to 0.2% of patients in the active comparator or placebo group. No severe or serious cases of hypoglycemia were reported. Hypoglycemia occurred in 1% of patients receiving vildagliptin as add-on to metformin, and in 0.4% of patients receiving placebo. Hypoglycemia occurred in 0.6% of patients receiving pioglitazone as add-on to vildagliptin, and in 1.9% of patients receiving placebo. Hypoglycemia occurred in 1.2% of patients receiving sulfonylurea with vildagliptin, and in 0.6% of patients receiving placebo.

When sulfonylurea and metformin were used, hypoglycemia occurred in 5.1% of patients receiving vildagliptin, and in 1.9% of patients receiving placebo. In patients receiving vildagliptin in combination with insulin, the frequency of hypoglycemia was 14% for vildagliptin and 16% for placebo.

Reporting suspected adverse reactions

Reporting of adverse reactions following medicinal product registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

14 tablets in a blister, 2 or 4 blisters in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Manufacturer's address and location of its business activity.

Sankaklar Quarter, Eskiakcakoy Avenue, No. 299, 81100 Duzce, Turkey.